Traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel lactam derivative of the commonly prescribed 1,4 dihydropyridine calcium channel blocker nifedipine (1-acetyl-2,4- dimethylbenzo[c][2,7]naphthyridin-5(6H)-one; NFD-L) that lacks calcium channel blocking capacity but significantly decreases Ass1-42 production by increasing levels of alpha-secretase (ADAM-10) and decreasing levels of presenilin-1 and nicastrin (components of the gamma secretase complex). Based on our preliminary data, the hypothesis to be tested in this proposal is that NFD-L lacks calcium channel blocking capacity and potential adverse cardiovascular side effects, effectively diminishes generation of A?1-42 by increasing levels of alpha-secretase (ADAM-10) processing of APP and by decreasing levels of proteins involved in A?1-42 processing (presenilin-1 and nicastrin), and improves spatial learning in a mouse model of amyloid deposition. In addition, we hypothesize that NFD-L does not lead to microhemorrhages or edema (amyloid related imaging abnormalities; ARIA) that are associated with immunotherapy mediated A? clearance. If successful, the data obtained in this proposal would further clarify the effects of NFD-L on A? processing and confirm whether or not it induces ARIA which would address FDA concerns and potentially increase the likelihood of successful commercialization of NFD-L. PUBLIC HEALTH RELEVANCE: Currently two classes of medications are FDA approved for use by Alzheimer's disease (AD) patients including cholinesterase inhibitors (Aricept) and an N-methyl-D-aspartate (NMDA) antagonist (Memantine). Although these therapeutics show clinical benefit in some patients, many do not respond. Additionally, these drugs do not significantly modify disease progression and perhaps more importantly are not approved for patients at earlier stages of the disease (mild cognitive impairment; MCI). For these reasons there is a critical need to identify additional therapeutics that can be initiated early in the disease progression to alter the pathogenesis of the disease. Preliminary and future studies described in this proposal aim to test the efficacy of a novel derivative of a commonly prescribed calcium channel blocker in a mouse model of amyloid beta (A1-42) deposition (APP/PS1 mice) and to determine if the novel therapeutic leads to microhemorrhages or edema as has been observed in studies using A immunotherapy. If successful, the results of the proposed studies would address concerns that have been raised by the FDA regarding amyloid lowering agents and further support testing of the compound in clinical trials.